Dermatitis is inflammation of the skin. Many forms and causes of dermatitis exist, including eczema, atopic dermatitis, allergic contact dermatitis, irritant contact dermatitis, psoriasis, seborrheic dermatitis, and photosensitivity dermatitis. The current invention relates to dehydroepiandrosterone-glucocorticoid combinations which are effective against these dermatoses.
Eczema is a general term for epidermal inflammation progressively characterized by erythema (redness), pruritis (itching), vesicular eruption, weeping, oozing, crusting, scaling, lichenification (skin thickening), and even increased pigmentation. Atopic dermatitis is an eczematous dermatitis in genetically predisposed individuals who have an abnormally low threshold for cutaneous pruritis and eruption.
Contact dermatitis is the most common form of dermatitis and can be either allergic, mediated by a sensitizer or allergen, or irritant. Contact dermatitis is an altered state of skin reactivity induced by exposure to an external agent (American Academy of Dermatology Association [AADA] 1995), chemical, animal, or vegetable, effecting perhaps 5 to 20% of Americans at some point in life. Allergic contact dermatitis is mediated by a delayed immune, or cell-mediated immune, response, while irritant contact dermatitis is caused by an inherently irritating property of a compound. Contact dermatitis can range in severity from a mild and short-lived, self-limited condition, to a “severe, persistent, job-threatening, and sometimes life-threatening disease” (AADA 1995). More than 2,800 substances have been identified as contact allergens (AADA 1995).
Poison ivy dermatitis is considered “the prototype allergic contact dermatitis” (Guin 2001), with the majority of Americans showing allergy to one degree or another. “Allergic contact plant dermatitis and poison ivy are nearly synonymous, at least in North America” (Juckett 1999).
Poison ivy and its relatives, including poison oak and poison sumac, are in the genus toxicodendron (“poisonous plant”) of the Anacardiaceae family (Crawford and McGovern 2002). Toxicodendron contact dermatitis results from reaction to an oil-soluble “oleoresin” (urushiol) that is dispersed throughout the plants and readily absorbed by human skin (Guin 2002). The oily allergen, urushiol, can be transferred from one part of the body to another and can survive on fomites (such as garden tools or clothing) for long periods.
The clinical presentations of poison ivy, or toxicodendron, allergic contact dermatitis are well known to most Americans. These include erythematous, pruritic (red, intensely itching), blistering lesions that are often streaked across skin expanses. Vesicles usually develop within 2-3 days after exposure to urushiol plant allergen; these vesicles easily break and release “plasma” or “weep” to form a crust (Juckett 1996). Large bullous lesions often develop. Intense itching is present as a core symptom in poison ivy dermatitis and can be debilitating. Reduced pruritis-related daytime concentration and pruritis-related insomnia are common. The scratching of poison ivy lesions can lead to secondary lesions.
Once generated, primary poison ivy dermatitis lesions are usually self-limiting and clear within 3-4 weeks. However, poison ivy dermatitis may last for months and can be severe, with intensely pruritic blisters covering substantial body surface or afflicting the genitals, face, hands, or feet (Goodall 2002). Poison ivy allergic dermatitis can also be systemic, as, for example, after inhaled smoke from burned poison ivy plants.
Glucocorticoid hormones, usually synthetic, are a mainstay of treatment for contact dermatitis in general, and also, accordingly, for poison ivy (urushiol) dermatitis (AADA 1995; Juckett 1996; Brodell & Williams 1999; Goodall 2002). Topical glucocorticoids are used for mild to moderate contact dermatitis (AADA 1995), including toxicodendron dermatitis outbreaks, or for outbreaks on limited skin areas. Topical treatment alone may be adequate for mild cases of contact dermatitis. Applications are usually made two times per day, although range from one to four or more times per 24 hours. Topical glucocorticoids may suppress symptoms of allergic toxicodendron dermatitis (such as poison ivy), but do not normally shorten the 2-3 week course of dermatitis.
Systemic glucocorticoids are indicated in those patients in whom extensive skin involvement is seen or in whom symptoms are severe enough to interfere with daily function (e.g., work relationships, or sleep) (AADA 1995; Juckett 1996; Brodell & Williams 1999; Goodall 2002). In poison ivy dermatitis, and contact dermatitis in general, systemic glucocorticoids are also sometimes prescribed in order to reduce the allergic reaction and severe itching that promotes scratching, subsequent secondary lesions, and prolongation of the episode in vulnerable individuals.
Oral glucocorticoid therapy for poison ivy dermatitis is usually recommended to begin with 30-60 mg/day of prednisone, or its equivalent in glucocorticoid potency (see Table 1), and to continue for 10-21 days (Resnick 1986; Juckett 1996; Guin 2001). Accordingly, Brodell and Williams (1999) recommend starting most adults with 60 mg/day of prednisone for four days, and then tapering the dose over the next two weeks. Altogether, for most adults, they recommend using 540 mg of prednisone over 14 days of treatment. A treatment period with glucocorticoids of at least 14 days is recommended because rebound dermatitis often occurs if the duration of glucocorticoid treatment is shorter (Brodell and Williams 1999). In this regard, the commercially available prednisone or methylprednisolone prepackaged dose packs that are commonly administered for poison ivy contact dermatitis provide a total of 105 mg of prednisone (or the roughly equivalent 84 mg of methylprednisolone) in a tapering dose over six days. For severe poison ivy dermatitis these prepackaged glucocorticoids do not provide an adequate dose and the course of treatment is too brief (Juckett 1996; Brodell & Williams 1999).
Approximate GlucocorticoidGlucocorticoidDose EquivalentCortisone  25 mgBetamethasone 0.7 mgDexamethasone0.75 mgHydrocortisone  20 mgMethylprednisolone  4 mgPrednisolone  5 mgPrednisone  5 mgTriamcinolone 0.8 mg
References: AHFS Drug Information 2001, American Society of Health System Pharmacists, Bethesda Md., 2001; Schimmer & Parker 2001
Glucocorticoids, the steroid hydrocortisone and its derivatives, are classical “stress hormones” and have catabolic (tissue breakdown) effects. Systemic adverse effects of glucocorticoids include bone demineralization (bone thinning), body fat redistribution (trunk obesity and “moon”-like [round] face), weakening of elastic tissues and muscle, and hyperglycemia (elevated blood sugar), among others.
In addition to their use in contact dermatitis, glucocorticoids—predominantly topical—are the mainstay for treatment of eczema, hand dermatitis, psoriasis, and atopic dermatitis (Green et al 2005, Leung et al 2004, Pearce et al 2004). However, there is currently inadequate information available regarding the treatment of hand eczema, which can vary in severity from mild inflammation to severe and incapacitating blistering, scaling, and/or cracking of the whole hand and all fingers (Van Coevorden et al 2004).
Topical glucocorticoids are currently still the most frequently used drugs in dermatologic practice (Brazzini and Pimpinelli 2002), even though they were introduced back in the 1950s (Lee 1981) and have significant adverse effects. Topical glucocorticoids are well known to cause local skin atrophy (thinning of the skin), purpura (bruised-appearing skin), striae (“stretch marks”), tolerance and “addiction syndrome” (Lee 1981; Rapaport and Lebwohl 2003). Chronic use of topical glucocorticoid is ideally avoided in the treatment of atopic dermatitis, due to side effects (Leung et al 2004). However, there are few good alternatives at present. The topical calcineurin inhibitors pimecrolimus and tacrolimus were introduced in the United States in 2001 and 2002, respectively, as an alternative to topical glucocorticoids in the treatment of atopic dermatitis, but, according to the U.S. Food and Drug Administration, these drugs share “a potential cancer risk” and, according to an FDA public health Advisory issued Mar. 10, 2005, should be used only as second-line agents for the short-term and intermittent treatment of atopic dermatitis in patients who have failed or are intolerant to other treatments (www.fda.gov/cder/drug/advisory/elidel_protopic.htm).
Dehydroepiandrosterone (DHEA), interconvertible with its sulfate, dehydro-epiandrosterone-sulfate (DHEA-S), and its derivatives (e.g., the 7-hydroxylated derivative), is an adrenocortical sex hormone precursor secreted, like the adrenocortical glucocorticoid cortisol with which it shares a similar circadian rhythm, in response to corticotropin (ACTH) released by the anterior pituitary (Bethune 1975; Rosenfeld et al 1975). The average daily production of DHEA in the human is approximately 25 mg per day (Bird et al 1978) whereas the average production of hydrocortisone is about 20 mg per day (or the equivalent of about 5 mg of prednisone or 4 mg of methylprednisolone). Supraphysiologic doses of DHEA (200 mg/day) have been reported to help treat the rheumatic disease systemic lupus erythematosus (SLE) (van Vollenhoven et al 1995). In this regard, Schwartz and Gurwith (2003) taught in U.S. Pat. No. 6,552,010 that systemic lupus erythematosus (SLE) can be treated by adding DHEA, of 100 mg per day or more, to a pre-existing drug regimen consisting of either a glucocorticoid, a non-steroidal anti-inflammatory, an immunosuppressant, or an anti-malarial drug.
DHEA is present in skin (Gallegos & Berliner 1967) and DHEA replacement in situations associated with low circulating DHEA concentrations, such as in adrenal insufficiency or aging, improves skin hydration, epidermal thickness, and sebum production (Baulieu et al 2000; Johannsson 2002).
The present invention teaches that combined glucocorticoid-DHEA treatment, in various formulations (oral, topical, etc) is an effective treatment for various forms of dermatitis and is a significant improvement over the current typical treatment of a glucocorticoid alone. The present invention teaches that co-administration of DHEA with a glucocorticoid hormone in poison ivy contact dermatitis (reaction to urushiol), hand dermatitis, eczema or atopic dermatitis, and psoriasis is effective, reduces symptoms such as pruritis and rash, and shortens the duration of the dermatitis.